Vaccination induces immunological memory and is the most effective means of preventing infectious diseases. The magnitude and kinetics of anamnestic antibody responses is directly proportional to the quantity and quality of antigen-specific memory B cells. Host interactions with bacterial pathogens result in far more complex immune responses compared to isolated bacterial components that are commonly incorporated into vaccines. To understand the complexity of immune responses to whole bacteria we previously utilized a bacterial infection system and discovered a novel role for B1b cells. While the specific antigens driving the protective B cell responses in these bacterial systems have been identified, e.g. Vi polysaccharide (ViPS) of S. Typhi, the molecular mechanisms governing B cell memory to these T cell-independent antigens remains to be understood. It is known that re-immunization with purified polysaccharides including ViPS and PPS results in hyporesponsiveness, leading to serious concerns about the effectiveness of booster strategies that are currently in practice for such vaccines. More recently, PPS- and VIPS-conjugate vaccination strategy has failed to induce booster responses in disease endemic regions. We have previously hypothesized that efficient T cell- independent B cell responses require engagement with both B cell antigen receptor and co-stimulatory receptors such as Toll-like receptors. Indeed, we found that ViPS-expressing bacteria induce enhanced ViPS- specific secondary IgM and IgG responses compared to primary responses, which is indicative of PS-specific B cell memory. In striking contrast, secondary responses to Typhim Vi, a vaccine composed of purified ViPS, severely impaired compared to the primary response indicating B cell hyporesponsiveness and the impact of this booster immunization strategy has never been determined in humans. S. Typhi is a human-restricted pathogen and does not productively infect commonly used inbred laboratory mice. This is a significant barrier to efforts to understand protective polysaccharide-specific memory responses against human typhoid. The S. Typhimurium infection system has been employed as a murine model of human typhoid. Using a novel chimeric strain of S. Typhimurium that was recently engineered to express surface characteristics of S. Typhi, we are able to demonstrate that the impairment in anti-VIPS responses correlates to more than an order of magnitude higher bacterial burden compared to whole bacterial immunization. Additionally, using a new and expansive panel of recombinant inbred mouse strains called the Collaborative Cross (CC) we have identified two independent CC mouse lines that can be productively infected with S. Typhi and develop histological features that are strikingly similar to biopsies taken from typhoid-infected humans. Preliminary results indicate that immunization of CC mice results in robust ViPS-specific antibody response. Collectively, these findings suggest that both the chimeric S. Typhimurium strain and CC mice can serve as novel in vivo translational platforms in which to assess the functional characteristics of polysaccharide-specific B cell responses.